PET imaging of somatostatin receptors:: design, synthesis and preclinical evaluation of a novel 18F-labelled, carbohydrated analogue of octreotide
PET imaging of somatostatin receptors:: design, synthesis and preclinical evaluation of a novel 18F-labelled, carbohydrated analogue of octreotide
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DOI：
10.1007/s00259-002-1012-1
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发表时间：
2003-01-01
影响因子：
9.1
通讯作者：
Schwaiger, M
中科院分区：
文献类型：
--
作者：
Wester, HJ;Schottelius, M;Schwaiger, M
由于氟-18的优良核性质和生长抑素受体（sst）PET显像的日益增长的兴趣，开发了一种新的碳水化合物F-18标记的sst配体并进行了临床前评价。N-α-（1-脱氧-D-果糖基）-N-双（2-[F-18]氟丙酰基）-Lys（0）-Tyr（3）-奥曲酸酯（[F-18]FP-Gluc-TOCA）的合成在类似于3小时内完成（20%-30%产率）。[F-19]FP-Gluc-TOCA对hsst 1和hsst 3无亲和力，对hsst 4（IC 50：437 +/- 84 nM）和hsst 5（IC 50：123 +/- 8.8 nM）有中等亲和力，对hsst 2有极高亲和力（IC 50：2.8 +/- 0.4 nM）。由于碳水化合物，发现[F-18] FP-Glue-TOCA的亲脂性较低（IG P-ow=-1.70 +/- 0.02）。在小鼠中，示踪剂通过肾脏排泄（肾脏：8.69% +/- 1.09%ID/g）快速清除，并显示肝脏（0.72% +/- 0.14%ID/g）和肠（1.88% +/- 0.52%ID/g）中的低摄取以及高肿瘤摄取（13.54% +/- 1.47%ID/g）（所有数据均在注射后1小时）。p.i. 60 min时的肿瘤与非肿瘤比率血、肝、肠、肾和肌肉的平均活菌数分别为25、19、7、1.6和56。在胰腺肿瘤大鼠中观察到类似的生物分布模式。通过共注射500 μ g Tyr（3）-奥曲肽，大鼠的肿瘤摄取分别降低至对照组（30和60 min）的36%和18%，证明了SST特异性摄取。在肝脏转移性类癌患者的第一项[F-18]FP-Gluc-TOCA-PET研究中，示踪剂显示出优越的上级药代动力学，例如快速尿排泄和肝脏、肾脏和脾脏的低摄取。多个肝脏病变（SUV范围为21.4 - 38.0）和先前未知的腹部局灶性摄取（SUV 10.0）清晰可见。这是第一份使用F-18标记的SST结合肽进行PET成像的报告;它表明[F-18]FP-Gluc-TOCA提供了优异的成像特性，并允许SST成像具有高肿瘤与非肿瘤对比度。
Because of the excellent nuclear properties of fluorine-18 and the growing interest in somatostatin receptor (sst) scintigraphy with PET, a novel carbohydrated F-18-labelled sst ligand was developed and preclinically evaluated. Synthesis of N-alpha-(1-deoxy-D-fructosyl)-N-epsilon(2-[F-18]fluoropropionyl)-Lys(0)-Tyr(3)-octreotate ([F-18]FP-Gluc-TOCA) was completed in similar to3 h (20%-30% yield). [F-19]FP-Gluc-TOCA showed no affinity to hsst1 and hsst3, moderate affinity to hsst4 (IC50: 437 +/- 84 nM) and hsst5 (IC50: 123 +/- 8.8 nM) and very high affinity to hsst2 (IC50: 2.8 +/- 0.4 nM). As a result of carbohydration, lipophilicity of [F-18]FP-Glue-TOCA was found to be low (Ig P-ow=-1.70 +/- 0.02). In mice, the tracer was rapidly cleared via renal excretion (kidneys: 8.69% +/- 1.09%ID/g) and showed low uptake in liver (0.72% +/- 0.14%ID/g) and intestine (1.88% +/- 0.52%ID/g) and high tumour uptake (13.54% +/- 1.47%ID/g) (all data at 1 h p.i.). Tumour to non-tumour ratios at 60 min p.i. reached 25, 19, 7, 1.6 and 56 for blood, liver, intestine, kidney and muscle, respectively. A similar biodistribution pattern was observed in pancreatic tumour-bearing rats. Tumour uptake in rats was reduced to 36% and 18% of control (30 and 60 min) by co-injection of 500 mug Tyr(3)-octreotide, demonstrating sst-specific uptake. In a first [F-18]FP-Gluc-TOCA-PET study of a patient with a metastatic carcinoid in the liver the tracer showed superior pharmacokinetics, e.g. rapid urinary excretion and low uptake in liver, kidney and spleen. Multiple liver lesions (SUVs ranging from 21.4 to 38.0) and previously unknown focal uptake in the abdomen (SUV 10.0) were clearly visible. This is the first report on PET imaging using an F-18-labelled sst binding peptide; it indicates that [F-18]FP-Gluc-TOCA offers excellent imaging characteristics and allows sst imaging with high tumour to non-tumour contrast.